Schizophrenia (SZ) is a complex genetic disorder with a lifetime risk of approximately 1%. Recent technological innovations have opened a new window into the genetic basis of SZ. Based on work by multiple groups using different approaches to examine genome-wide association (GWA), and the association of copy number variants (CNVs) and single nucleotide polymorphisms (SNPs) with SZ, multiple risk factors have been definitively identified. They can now be studied experimentally to understand their molecular and neurobiological effects. These risk factors include individually-rare mutations that confer high risk as well as common genetic variants that confer modest effects. Here, we hypothesize that defects in multiple genes that are diverse in their individual functions, but interact within the context of cellular pathways are important for SZ pathogenesis. To test this hypothesis, we propose to investigate SZ from the systems biology perspective with the aim of defining protein interaction networks and functional modules that are relevant to the disease. To achieve this goal, we propose an integrative approach to build SZ protein-protein interaction network (i.e. SZ interactome) that includes SZ risk genes, their brain splice variants and mutant transcripts of the genes that are disrupted by the breakpoints of genomic deletions and duplications in SZ patients. The specific aims are as follows. (1) Perform a large-scale discovery of brain alternatively spliced isoforms of SZ gene candidates using our recently developed high-throughput isoform discovery pipeline that incorporates parallel 454 FLX sequencing and computational analysis platforms; (2) Identify and clone mutant transcripts of the genes disrupted by the breakpoints of genomic deletions and duplications in SZ patients; (3) Build an interactome of SZ candidate genes, their alternatively spliced variants and mutant transcripts to define key functional modules involved in SZ pathology. The results of this study will make substantial contributions to knowledge of the cellular pathways that underlie schizophrenia. PUBLIC HEALTH RELEVANCE: The results of this study will make substantial contributions to our knowledge of the causes of schizophrenia and of cognitive development. The discovery of functional modules that connect schizophrenia candidate genes, their splice variants and mutants is an important step towards understanding the mechanism of disease development. The final goal of this project is to define specific schizophrenia-relevant protein interactions that could be targeted therapeutically.